Methyl donors - SAMe, TMG + any others ie DMG

Is P5P a methyl donor? I've heard some people say it is and others say it isn't.

Source Naturals has a reasonably priced P5P sublingual. It's only 25mg, but since it's a sublingual it's absorbed better than taking it orally. It's large enough that it can be cut in half or even quarters if someone wants to take a low dose and/or spread it out throughout the day.

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No P5P is not a methyl donor.

But it is crucial to making methylfolate (by making the methylene intermediate, riboflavin-5-p controls the final step), to making methionine with the methionine synthase enzyme, to making dopamine and serotonin. to making gaba, to breaking down glycogen, and to regulating the trans-sulfuration pathway.

From experience if you use the sublingual from Source Naturals and place it under the upper lip and have it stay there for a long time (like methyl B12 sublinguals with Freddd protocol) then the equivalent dose is stronger than say a Solgar oral P5p supplement? The relative ratio? Dunno for sure by maybe 50-100% stronger from my best guessing.

But it is crucial to making methylfolate (by making the methylene intermediate, riboflavin-5-p controls the final step), to making methionine with the methionine synthase enzyme, to making dopamine and serotonin. to making gaba, to breaking down glycogen, and to regulating the trans-sulfuration pathway.

From experience if you use the sublingual from Source Naturals and place it under the upper lip and have it stay there for a long time (like methyl B12 sublinguals with Freddd protocol) then the equivalent dose is stronger than say a Solgar oral P5p supplement? The relative ratio? Dunno for sure by maybe 50-100% stronger from my best guessing.

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So P5P could potentially cause problems for those sensitive to methylfolate?

So P5P could potentially cause problems for those sensitive to methylfolate?

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P5p will stimulate the body's own production of methylfolate and will also stimulate the methylation cycle and the conversion of homocysteine to cystathione via the CBS enzyme. Not to mention it affects a ton of other reactions in the body.

When you say "sensitive", generally the premise is the individual reacts negatively to the increased rate of production of one or products or stages of the aforementioned cycles as the system is not in balance.

But these are chemical reactions at chemical equilbrium to one another. So you may find that doubling your P5p will have far less impact on the methylation cycle than say increasing methyfolate even slightly. But someone with the CBS mutations upregulating the trans-sulfuration pathway may find both changes intolerable. On the other hand someone who is low in dopamine and serotonin who is deficient in P5p may find it a remarkable thing.

In other words, if P5p is not the rate limiting step then adding more will not exacerbate the problems but could impact other reactions. Btw what most people miss on these forums is R5p (riboflavin 5 phosphate) is often the rate limiting step to making your own methylfolate from the methylene intermediate. Ironically everyone focuses on P5p due to its role in methionine synthase and emphasize supplementing 5mthf. But if your MTHFR gene is not defective with a C667 mutation then r5p is probably the rate limiting step and too much could flood your methylation cycle if you can process your folates from vegetables well enough.

Personally I have found methylfolate (and r5p) to be a big lever arm (both good and potentially bad) when it comes to my health. But I may have a different genetic profile than many on these forums. What saddens me is I see many people on these forums who show signs of overmethylation because they are trying to follow the same steps of people who have MTHFR c667 mutations that deplete their own production of methylfolate. But if someone like myself, has only the a198c mutation then they really risk overdriving their system, and yet the people for whom methylfolate is essential claim it is 'sensitivity' or even 'start up' effects, and so the person valiantly struggles taking larger doses than they should and wonders what is wrong. What is good for the goose may not be for the gander, right? The problem is this can occur at other stages in the key cycles of interest as well, so you can have a difficult multi-factorial problem.

On that note I find a huge positive difference taking 200 mcg (with no vitamin C) than taking no methylfolate or even taking 400-800 mcg with vitamin C (vitamin C kills the absorption in the gut if taken simultaneously). On the other hand if I take without vitamin C: 800 mcg of methylfolate, 800 mcg of folinic acid, 500 mg of TMG and even worse on top of that some SAMe, then I am definitely swung the other way to overmethylation, and my A1298c mutation doubly screws me since it means I cannot feedback downregulate my own generation of methylfolate, leading to irritability, insomnia, pain, reflux, etc. Things are even more complicated if you have COMT polymorphism that means SAMe stays around longer since it is not being used at a fast enough rate to metabolize dopamine and norepinephrine, the latter of which can really harm the body if overloaded constantly.

I suppose this is why there are different protocols. Freddd's is very high in methylfolate and mb12 and is probably more suited for people with the relevant MTHFR and MTR mutations. While Rich Vank's is for those of us who have partial blocks but a different set of mutations.

If you really want to find out if you are overmethylating at given dose of 5mthf, do one of two things, either a) take it with vitamin C (which should neutralize it almost entirely if you take large enough vit c dose) or b) take some niacin or even niacinamide and see if the negative effects damp down. (b) is probably less invasive as a) will reduce the methylfolate quite a bit. For my own part it was the vitamin C link that proved the overmethylation of myself for almost two years trying to follow something like Dr Myhill's protocol that was obviously not working for me (did more harm than good).

So to answer your question, unless p5p is the rate limiting factor in one of the key steps of the folate or methylation cycle it should not cause problems unless you take a high dose. This may not be true for those with a CBS mutation where the dose would need to be even lower. But it is also really, really bad to be deficient in p5p. My modus operandi is to not take a multivitamin with B6 and control my own input of P5p directly.

Dr Yasko suggests something like 12.5 mg of p5p per day (I think) regardless of mutations. Some may benefit from higher doses provided they don't activate other things. Seems hard to believe 12.5 mg will overstimulate the key cycles unless the person is way overdosing on other things.

I felt some extra overmethylation at 50-75 mg looking back but it was nothing like switching from 50 mg of riboflaviin to 50 mg of riboflavin + 50 mg of riboflavin 5 phosphate (the latter which is MUCH better absorbed by the body breaking the 30 mg linear saturation threshold) or even when I added SAMe which with my COMT mutations meant I got 3-4 hours of sleep every night regardless of taking klonopin and 5htp + free form glycine to sleep. Felt like I could conquer the world but was way to over-driven and pain got worse.

Anyways I apologize if I rambled I am sick right now with a nasty head cold courtesy of my daughter. I would just suggest if one angle to the problem is constantly being obstructive look for another angle that might help you get around things. Also the proper genetic and other diagnostic information I think is essential for trying to resolve these problems. I am highly dubious one protocol can work for everyone given the complexity of the chemical reactions involved and their importance to the body.

I suppose this is why there are different protocols. Freddd's is very high in methylfolate and mb12 and is probably more suited for people with the relevant MTHFR and MTR mutations. While Rich Vank's is for those of us who have partial blocks but a different set of mutations.

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I agree that many seem to be taking far too high doses of MTHF. I have myself taken 3-5mg of MTHF for about 6 months, along with MB12, P5P, R5P, TMG, choline. It was way too much, and there was no end in sight of any sensitivity calming down, or a "detox" reaction ending. That's because it wasn't sensitivity or detox, but simply pure overmethylation.

One question I can't seem to get my head around, is why would anyone need to take more than 400mcg of MTHF? In the case of being heterozygous for C677T, MTHF would be at aprox. 70%. If homozygous, it would be at about 30%. But even if it were at 0% production, supplementing 400mcg would supply the entire RDA. Is it because of defects in absorption, or what is the reason anyone would need to take more?

Regarding P5P, I must add that even though I have CBS upregulation, I do feel better on moderately high doses of P5P (70mg ATM). After increasing my dose of MB12 I felt I really needed it to counter the extra stimulation, perhaps of the conversion of glutamate to GABA.

I agree that many seem to be taking far too high doses of MTHF. I have myself taken 3-5mg of MTHF for about 6 months, along with MB12, P5P, R5P, TMG, choline. It was way too much, and there was no end in sight of any sensitivity calming down, or a "detox" reaction ending. That's because it wasn't sensitivity or detox, but simply pure overmethylation.

One question I can't seem to get my head around, is why would anyone need to take more than 400mcg of MTHF? In the case of being heterozygous for C677T, MTHF would be at aprox. 70%. If homozygous, it would be at about 30%. But even if it were at 0% production, supplementing 400mcg would supply the entire RDA. Is it because of defects in absorption, or what is the reason anyone would need to take more?

Regarding P5P, I must add that even though I have CBS upregulation, I do feel better on moderately high doses of P5P (70mg ATM). After increasing my dose of MB12 I felt I really needed it to counter the extra stimulation, perhaps of the conversion of glutamate to GABA.

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Yeah the sensitivity and detox card I personally feel gets played way, way too often.

It is like someone who doses high on Cytomel and their heart pounds and they can't sleep for days and telling them their adrenals are 'sensitive' to T3 .... yeah right (done that btw with Cytomel, makes overmethylation look tame in comparison).

I think your logic stand for the heterozygote. I am not sure about the 30% number for the homozygote as I think they are rules of thumb guidelines and some people have nasty MTR / MTRR mutations also. I think folic acid is a bad thing. I think for many they will convert folinic acid to the methylene intermediate no problem and the question is how good are they at converting to 5mthf modulated by R5p (most people on these forums think P5p does that, P5p is the THF to methylene intermediate step, while folinic acid is a 'back door').

Also remember some people on here are taking their methylfolate with vitamin C (kills absorption when taken in 20 minute or so time window and especially when simultaneous) and other take high amounts of B3 for energy (which mops up methyl donors). So that might affect things also.

I think Rich hit the nail on the head for many who have reasonable genetics but have functional blocks. I don't agree with everything he suggested but the 200 mcg or so of 5mthf and up to 400 mcg is reasonable for many.

Freddd's story is inspirational for someone who has been dealt an extremely bad set of genetic "cards" but some of the amounts used will just wipe people out and I am sorry detox / startup is not the issue there imo (I too learned the hard way).

Now that I know I have the A1298c mutation I realize now I am very susceptible to over-methylation because I convert folates fine (I eat a lot of vegetables, etc.) and with the reduced binding to the feedback inhibitory domain of SAMe on the MTHFR gene, I can't down-regulate that when methylation is high, not to mention the COMT gene at the other hand (can't even imagine a COMT +/+ trying Freddd's protocol, be like skating on thin ice regardless of their MTHFR mutations).

Personally I am finding that 400 mcg 5mthf without vitamin C and still taking 500 mg niacinamide will over-stimulate me and by the third day it builds to insomnia. 200 mcg seems more tenable (though the damn pills are hard to cut). But that is me.

I think mb12 is great, I am not sure I buy into the hydroxy b12, but high mb12 will kill melatonin and induce restlessness. I take a crumb of adb12 per day now. I used to take 1/4 Source naturals every day and at first it made me really sleepy, then amped me like crazy. And that was for several months. That is not a start-up effect. Period.

Remember methylation will also increase glutamate in the body. No one on here likes to talk or hear about that. It does it by the THF (in the folate loop) processing histidine into a form of glutamate instead of histamine. This is the reason why over methylators get stimulated and have low histamine levels.

P5p is involved in a gazillion processes in the body. If you have CBS you are probably draining more methyl donors (SAMe especially) down the trans-sulfuration pathway. Maybe that helps you. But p5p is critical to the krebs cycle and the GABA conversion (which for me is killed by my antibodies but that is another matter). But it also helps to make dopamine and serotonin.

Again the issue is what is the rate limiting factor. If you have low BH4 but lots of P5p taking more p5p will not increse dopamine and serotonin. If you have lots of BH4 and are low P5p then bam those neurotransmitters will rise a lot unless you are deprived in (tyrosine, iron) or tryptophan. For those people an explosion of norepinephrine may not be welcome.

I am not sure based on what you have posted though on other threads that glutamate is your prime issue. Mg glycinate should calm you somewhat if that were the case. And yet you say NAC calms you down which should be really a big load on the sulfur processing pathways. So not clear to me.

I used to take 50-75 mg of P5p. Now I am down to 12.5mg of a sublingual and doing better (less pain, less irritability, less broken sleep (though dreams less crazy vivid of course). But maybe I will go back to 25. The sublingual I use is coenzymated and I milk it forever under my upper lip so I probably get more than the oral equivalent.

a) Yasko is wrong and CBS pathway does not directly make AKG, it is AKB (very different) so glutamate is not a direct product of trans-sulfuration to my knowledge.

b) glutamate can be the result of poorly functioning glutamine synthetase (synthase?) which has biotin and Mn as cofactors (though Mn has been shown to raise glutamate in some cells in rats in that paper I linked in the other thread).

a) Yasko is wrong and CBS pathway does not directly make AKG, it is AKB (very different) so glutamate is not a direct product of trans-sulfuration to my knowledge.

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Sorry, I don't know where you're going with this? This is related to P5P, or?

b) glutamate can be the result of poorly functioning glutamine synthetase (synthase?) which has biotin and Mn as cofactors (though Mn has been shown to raise glutamate in some cells in rats in that paper I linked in the other thread).

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Aha. What a revelation. Never really felt anything from Mn, but since I started taking extra biotin a few days ago, I've had a huge increase in energy. I usually have a protein drink in the morning with about 40g of egg protein (from whites). I have perhaps been depleting my biotin without even knowing it.

The biotin also seems to improve tingling and leg strength/standing. This all fits with my theory that my glutamate signaling is low, at least in some parts. Glycine and taurine both seem to worsen my OI, glycine much more than taurine, though. On the other hand, NAC and magnesium do not have this negative effect on OI. Maybe it's because they function more like modulators than actual inhibitors.

But I must say that I also get problems with overstimulation, anxiety, tachycardia, jitteryness, pain, increased SNS symptoms, irritability, anger, slight OCD, focus problems. Still my main theory is that the ACh overload I experienced, caused hyperstimulation of the NMDA receptors. So either it's the ACh receptors or NMDA receptors which are burned. I also found that after stopping CDP-choline a few days ago, tingling, burning and fasciculations (especially in the legs) have increased.

I'm trialling magnesium threonate at the moment, and so far the effects have been fantastic. Much more calm, better mood, better focus, less pain, tingling, burning, anxiety, irritability, OCD aso. It really seems to hit the NMDAs much better than average magnesium forms. I hope it continues.

How do take your B vitamins? I take my MB12 (2mg) in the morning when I wake up. About 30 mins later I take 1 x Thorne Basic B complex with breakfast. I take another one with dinner. So far I have been taking them both with 1g of vitamin C. Each cap has 200mcg of MTHF and 200mcg of folinic, along with 150mg niacinamide and small doses of MB12/ADB12. Would it be better to take it on a empty stomach along with the B12? Or with breakfast and just take the C later? Maybe 800mcg folate is too much, without the C. Perhaps I should just take one in the morning?

And also, do you have any idea what's causing the drop in potassium when taking methyl donors?

Sorry, I don't know where you're going with this? This is related to P5P, or?

Aha. What a revelation. Never really felt anything from Mn, but since I started taking extra biotin a few days ago, I've had a huge increase in energy. I usually have a protein drink in the morning with about 40g of egg protein (from whites). I have perhaps been depleting my biotin without even knowing it.

The biotin also seems to improve tingling and leg strength/standing. This all fits with my theory that my glutamate signaling is low, at least in some parts. Glycine and taurine both seem to worsen my OI, glycine much more than taurine, though. On the other hand, NAC and magnesium do not have this negative effect on OI. Maybe it's because they function more like modulators than actual inhibitors.

But I must say that I also get problems with overstimulation, anxiety, tachycardia, jitteryness, pain, increased SNS symptoms, irritability, anger, slight OCD, focus problems. Still my main theory is that the ACh overload I experienced, caused hyperstimulation of the NMDA receptors. So either it's the ACh receptors or NMDA receptors which are burned. I also found that after stopping CDP-choline a few days ago, tingling, burning and fasciculations (especially in the legs) have increased.

I'm trialling magnesium threonate at the moment, and so far the effects have been fantastic. Much more calm, better mood, better focus, less pain, tingling, burning, anxiety, irritability, OCD aso. It really seems to hit the NMDAs much better than average magnesium forms. I hope it continues.

Again, I don't really understand what you're saying. Lost in translation here, lol.

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The comment regarding AKB is that Yasko mistakenly states that cysteine is turned into alpha-keto-glutarate by the body when energy demands are high. This is not correct. The result is AKB or alpha-keto-butyrate. The mistake by Yasko and other has permeated the web and so people justify CBS up-regulation as a natural source of glutamate by virtue of alpha-keto-glutarate. But as I said it is AKB not AKG. AKB has a long link of steps through propionyl COA and methylmalonyl COA and others to end up at succinic acid in the Krebs cycle. I think Rich Vank pointed this out in another thread somewhere, but virtually everyone keeps propagating the error I mentioned.

The point was to clarify that CBS problems don't directly jack up glutamate as has been listed on many threads on this forum. This doesn't mean CBS up-regulation can't cause excitation but it is through other channels.

On the biotin front, to clarify I meant that biotin and Mn are co-factors to convert glutamate into glutamine. While glutamate is an excitatory neurotransmitter, glutamine is also very important as a transport shuttle for glutamate in and out of the brain and is also very high in skeletal muscle. Glutamine helps with immune regulation, is the major source of energy for the gut lining and prevents catabolism in muscles. So I did not mean to imply that biotin increases glutamate.

Mn on the other hand in some tissues in animal studies has been shown to increase glutamate at the neurons, while lowering GABA. This however, may not mean that Mn generates a net total more glutamate in the body, in fact the glutamine synthetase suggests otherwise, BUT it may alter transport of glutamate in terms of extracellular vs intracellular spaces around the neurons (in some tissues; in animal studies ... lol sorry for all the disclaimers I need to learn more on this front myself).

The big thing about biotin and why you may feel more energy is maybe something else entirely. Biotin replenishes one of the most important anaplerotic reactions (http://en.wikipedia.org/wiki/Anaplerotic_reactions) in the body via pyruvate carboxylase to make oxaloacetate in the Krebs cycle. I think it can also help to make malate as well (not sure). Biotin also is a co-factor in the reaction steps to take propionyl COA eventually into the Krebs cycle via the other back door at succinate. Its being a co-factor of glutamine synthetase is not entirely verified to my understanding, it is based mostly on the premise of homology models (http://www.uniprot.org/uniprot/P15104).n

On that note you might want to experiment with either creatine pyruvate (if your kidneys are fine) or calcium pyruvate. I have found those along with d-ribose to be excellent for energy. In fact I would not be able to work without them. Period.

I myself have noticed an energy bump by adding back in 1000 mcg a day of biotin. Then again I have gotten a further bump by adding back in B1 (also critical to the front door of the Krebs cycle) which used to make me tired in the past (odd eh?).

Glycine will inhibit parts of the CNS especially in the spine which may be very relevant for you at this point, meaning you don't want that. Maybe taking Mg glycinate at night is not bad to settle down but based on what you have posted on several threads I would not use it during the day if I were you. We don't all have the same problems

Taurine may already be high enough in you with your CBS gene. You should try to check with a UAA at some point (though make sure you get a reading of beta-alanine as well). Taurine can also I think shunt sulfur down the cysteine pathway. I wonder though if your thesis is to reduce NMDA activity why taurine is poor for you unless it is TOO inhibitory and blocking some other signaling.

What I can't figure is why NAC is so good for you except that it is knocking down glutamate by virtue of the glutathione drain. That would suggest glutamate can be an issue for you. Yet you claim you think you are low in glutamate. Something doesn't fit imho.

Maybe it is a question of balance and whether we are talking glutamate in the brain or in the periphery. The nice thing about boosting glutamine synthetase activity is you allow your body to better balance what it needs especially in the brain. Excess build ups of glutamate in the brain are bad and the MAIN way to rectify this is push the gradient to glutamate or GABA synthesis. The latter for inhibition, the former to use the nifty glutamine shuffle between brain and body. So you may benefit from glutamine moving out to the body, and some conversion (usually 25%) to glutamate in the periphery may be beneficial while lowering glutamate in the brain, i.e. a new equilibrium.

This all highly speculative but if I were you I would keep on the biotin, I certainly plan on it. I am not a big fan of boosting manganese, but I would suggest being deplete is a bad thing as with any mineral. Copper is easy for us to come by in modern society. Manganese will depend on your diet methinks.

The CDP-choline may be helping your nerve sheaths or it may be due to stabilization of ATP pump activity which is one of the single most important things in your body (and most people, doctors included, usually don't talk about it). ATP is the currency of energy and the pumps are about maintaining sodium and potassium relative concentrations which is hugely intrinsic to cellular function and doubly so in neurons. One of the easiest ways to mess with neuronal signaling is to imbalance electrolytes. This is also where hormones in the form of aldosterone and T3 come into play as well. If those are low your pump activity is going to suffer.

A lot of your other symptoms kind of smack of norepinephrine to me. I have some of those issues as well by they are better controlled by my corticosteroids now so they are not my major complaint. Glutamate has nothing to do with tachycardia. So we are either talking norepinephrine or ACh as both relate to dysautonomia.

To be honest if you really think dysautonomia is a major things (POTS, OI, etc.) then you should really, really get your aldosterone, renin cycle checked out. Even if they are ok, you might want to contemplate Florinef and sea salt (to reasonable levels). To my understanding it is the front line in treating those disorders. It certainly fixed the OI in my brother and I. Some things will not fix with simply mineral or vitamin supplements. Just my opinion.

I am not aware of strong direct connections between ACh and NMDA. This goes back to my question in the other thread, is pain a major problem for you? If it is NMDA may be complicit. If pain is not, I doubt NMDA is you major problem. And I don't mean tingling. I mean pain.

Fasciculations can be due to many things including electrolyte imbalances (#1), high over stimulation by norepinephrine, ACh signaling problems, NMDA problems, hypo or hyper thyroid (if bad enough), as well as other factors.

A catabolic state (over active SNS) lends itself to fasciculations and pain via norepinephrine over-drive; a complicated inter-connection with the immune system that I don't have time to explain right now. I eat 4000 calories a day and can't gain weight above 155 lbs (I am a 6' 2" male). I would kill for 20-25 lbs.

I am glad to hear about the Mg threonate. Could you link your source? I would be interested.The best for plugging NMDA are supposed to be Mg taurate, Mg threonate, and

Citrate has its issues and during the day I would like to take less glycinate. Oxide is worthless. I use malate but that is only so I can take, and alternatively taurate may not be good for me either since my levels in the past have been really off the charts high (a sign not only of CBS dysregulation but an ongoing inflammation war that never ends). I do best when I get 1200-1400 mg of Mg a day. No more 400 of that can be citrate, 200 malate. So now I take 800 or so in glycinate which I would like to experiment reducing.

Sorry for not clarifying the AKG vs AKB information. I just see a lot of misinformation on these forums so when I remember I try to do what I can to clear things up as best I can.

On that note you might want to experiment with either creatine pyruvate (if your kidneys are fine) or calcium pyruvate. I have found those along with d-ribose to be excellent for energy. In fact I would not be able to work without them. Period.

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I have a 4-year old organic acid test, back from when this crap started. It says I have very high pyruvate levels. I have had problems with kidney stones and high creatinine, also.

Glycine will inhibit parts of the CNS especially in the spine which may be very relevant for you at this point, meaning you don't want that. Maybe taking Mg glycinate at night is not bad to settle down but based on what you have posted on several threads I would not use it during the day if I were you. We don't all have the same problems

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Yes, I take only at night.

What I can't figure is why NAC is so good for you except that it is knocking down glutamate by virtue of the glutathione drain. That would suggest glutamate can be an issue for you. Yet you claim you think you are low in glutamate. Something doesn't fit imho.

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I am more suggesting, than claiming anything. I am very confused about all this. I suspect I have cyclothymia, although I have never been diagnosed. I have always had mood cycling, and many substances can make me hypomanic. This includes too much TMG, alcohol, and many others. I think there is a problem with ion channels involved in bipolar disorders, this probably means my glutamate is unstable, perhaps fluctuating. This is just a guess though. To be fair, I've taken NAC so long I can't remember how I felt without it. Maybe it's time to give it a break.

Maybe it is a question of balance and whether we are talking glutamate in the brain or in the periphery. The nice thing about boosting glutamine synthetase activity is you allow your body to better balance what it needs especially in the brain. Excess build ups of glutamate in the brain are bad and the MAIN way to rectify this is push the gradient to glutamate or GABA synthesis. The latter for inhibition, the former to use the nifty glutamine shuffle between brain and body. So you may benefit from glutamine moving out to the body, and some conversion (usually 25%) to glutamate in the periphery may be beneficial while lowering glutamate in the brain, i.e. a new equilibrium.

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I have been thinking along these lines, too. I am not sure I understand how you suggest I achieve this?

A lot of your other symptoms kind of smack of norepinephrine to me. I have some of those issues as well by they are better controlled by my corticosteroids now so they are not my major complaint. Glutamate has nothing to do with tachycardia. So we are either talking norepinephrine or ACh as both relate to dysautonomia.

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Potassium helps the tachycardia. Sometimes sodium is needed also. But you are right, NE is a problem. I often have cold limbs, anxiety, tachycardia. When I take a bath my skin wrinkles very easily. ALCAR also reduce my tachycardia, so it leads me back to thinking about neuropathic autonomic (nicotinic) ganglia.

To be honest if you really think dysautonomia is a major things (POTS, OI, etc.) then you should really, really get your aldosterone, renin cycle checked out. Even if they are ok, you might want to contemplate Florinef and sea salt (to reasonable levels). To my understanding it is the front line in treating those disorders. It certainly fixed the OI in my brother and I. Some things will not fix with simply mineral or vitamin supplements. Just my opinion.

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I just looked at a 3 year old blood test. The doctor told me my aldosterone was normal, but I can see that it is in fact low. There are 2 results, with 8 mins between. Not sure why this is. The first result is 0.18 nmol/L, second 0.23. The reference is 0.19–0.83 nmol/L. Looks like I should have another test. I believe angiotensin is low. Angiotensin II antagonists and ACE inhibitors makes me worse. Coffee helps (though I get some SNS overstimulation), probably by stimulating angiotensin. Seems like a double edged sword. I need to "stim" to get the angiotensin up, but at the same time overload other systems. Please stop me if I'm babbling, lol.

I must say that I'm not willing to go on a steroid again at this point. Like I said, at physiological doses or HC, the skin was atrophying like crazy. I have also seen steroids kill my mother. She had Crohns and was on steroids for 15-20 years. She died at 60, about the size of a Golden Retriever. Just getting down on her knees was enough to cause a hip fracture. Not to talk about bleeding skin, infections that wouldn't heal aso. Can't I just take more pregnenolone or something, lol? There must be a reason why the aldosterone is low. It makes more sense to fix the cause of it, rather than taking steroids the rest of my life. I know this is easier said than done, lol.

Anyways, the OI is not nearly as bad as it used to be. So it seems it's possible to improve withouts steroids. I am in fact doing much better now than I ever did on HC. It didn't really help that much. I couldn't have gone to the gym on HC, but I can now, even though it is difficult and I have to sit down a lot. I have at least 24 hours of tachycardia, anxiety and increased pain after a workout. But I do not seem to have the severe malaise I used to have.

I do take sea salt. Quite a lot. 1/2 teaspoon per liter, plus I salt my food heavily. I think I'd be dead without the salt, I need it that bad, lol.

I am not aware of strong direct connections between ACh and NMDA. This goes back to my question in the other thread, is pain a major problem for you? If it is NMDA may be complicit. If pain is not, I doubt NMDA is you major problem. And I don't mean tingling. I mean pain.

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Excess ACh will cause excitotoxicity through NMDA. This is well known. Yes, I do have pain. I get pain from typing, for example. I've had very serious RSI, where my hands turned purple, freezing cold, and I couldn't move my fingers, plus tremendous pain. I'm better now, but yeah I have some pain. I just suck it up, I guess. It's not screaming pain, though.

A catabolic state (over active SNS) lends itself to fasciculations and pain via norepinephrine over-drive; a complicated inter-connection with the immune system that I don't have time to explain right now. I eat 4000 calories a day and can't gain weight above 155 lbs (I am a 6' 2" male). I would kill for 20-25 lbs.

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The thing is, it's very easy for me to gain weight. Not muscle though, this is hard. But gaining fat is very easy for me.

I am glad to hear about the Mg threonate. Could you link your source? I would be interested.The best for plugging NMDA are supposed to be Mg taurate, Mg threonate, and

I have a 4-year old organic acid test, back from when this crap started. It says I have very high pyruvate levels. I have had problems with kidney stones and high creatinine, also."​

Understood about the pyruate you are all set there then. Just make sure you get enough biotin, B1, carnitine, etc. to make use of it well.

I am more suggesting, than claiming anything. I am very confused about all this. I suspect I have cyclothymia, although I have never been diagnosed. I have always had mood cycling, and many substances can make me hypomanic. This includes too much TMG, alcohol, and many others. I think there is a problem with ion channels involved in bipolar disorders, this probably means my glutamate is unstable, perhaps fluctuating. This is just a guess though. To be fair, I've taken NAC so long I can't remember how I felt without it. Maybe it's time to give it a break.​

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Again I re-iterate that one of the major effects of NAC if it calms you down may be that it clobbers glutamate pretty efficiently. Clearly over sulfuration is not a big problem for you or you would get nasty effects (NAC makes me reflux pretty hard for example). That is a NMDA link for sure.

I have been thinking along these lines, too. I am not sure I understand how you suggest I achieve this?​

My suggestion with glutamine synthetase is to get the bad boy working better. That would mean biotin, Mg and (maybe) Mn. At least make sure you are not Mn deplete. If you add any Mn start with baby dose like 2.5 mg or so.

Potassium helps the tachycardia. Sometimes sodium is needed also. But you are right, NE is a problem. I often have cold limbs, anxiety, tachycardia. When I take a bath my skin wrinkles very easily. ALCAR also reduce my tachycardia, so it leads me back to thinking about neuropathic autonomic (nicotinic) ganglia.​

Norepinephrine can be a problem for a whole host of reasons, HPA, adrenals, low cortisol and the most likely candidate which is immune system dysregulation (including gut dysbiosis).

If ALCAR is helping your tachycardia it might be because it helps you get more effective use of your Krebs cycle and thus your body turns less to back up energy sources of which norepinephrine signaling is meant to be the last resort (of course that is often not the case in today's modern society).

If you think instead it is beneficial at a CNS level you could test this by taking regular L-carnitine or L-carnitine fumarate (don't take the tartrate that stuff is BAD news since it kills the malate shuffle). The other two won't cross the BBB while ALCAR does. That way you could differentiate your hypothesis.

I just looked at a 3 year old blood test. The doctor told me my aldosterone was normal, but I can see that it is in fact low. There are 2 results, with 8 mins between. Not sure why this is. The first result is 0.18 nmol/L, second 0.23. The reference is 0.19–0.83 nmol/L. Looks like I should have another test. I believe angiotensin is low. Angiotensin II antagonists and ACE inhibitors makes me worse. Coffee helps (though I get some SNS overstimulation), probably by stimulating angiotensin. Seems like a double edged sword. I need to "stim" to get the angiotensin up, but at the same time overload other systems. Please stop me if I'm babbling, lol.​

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I must say that I'm not willing to go on a steroid again at this point. Like I said, at physiological doses or HC, the skin was atrophying like crazy. I have also seen steroids kill my mother. She had Crohns and was on steroids for 15-20 years. She died at 60, about the size of a Golden Retriever. Just getting down on her knees was enough to cause a hip fracture. Not to talk about bleeding skin, infections that wouldn't heal aso. Can't I just take more pregnenolone or something, lol? There must be a reason why the aldosterone is low. It makes more sense to fix the cause of it, rather than taking steroids the rest of my life. I know this is easier said than done, lol.​

Beyond easier said than done. Hormones are very complicated. Unless you are working with a good physician I have no clue to predict what more pregnenolone will do for you. It is the mother hormone one step removed from cholesterol. It could do just about anything in the steroid space.

If HC was making your skin atrophy then I would suspect there is another player involved. Either you don't metabolize it well or the half-life is too long or you have defective 11 beta HSD enzymes or you have an immune function antagonist (i.e. infection or other condition). Not trying to spook you but 24-30 mg HC should not do that.
Considering what your mom went through you may have a genetic factor no one understands and yeah I would stay the heck away from glucocorticoids.

But ... don't necessarily lump aldosterone in that mix. Hear me out.

Most doctors don't know how to assess aldosterone level correctly. My Mom had several readings of 5-7 (scale 0-30) but she was borderline hyponatremic and really low potassium, but the doctors said normal. I finally convinced her, when she had bad arrhythmias, was blacking out, tachycardia and extreme emotional disturbances with terrible norepinephrine surges, to go to the hospital and ask for Na IVs and extended KCL tablets, she completely came back. She would go home and the cycle repeated. I told her to bring up Florinef with the doctors since if her salt is low and her aldosterone is low something is clearly screwed up and they of course refused. Finally I got her, after the third cycle,. to go to another doctor and he gave her Florinef in a small escalating dose + some extended release KCL and her heart is solid as a rock now. Her NE surges dropped, she sleep 7-8 hours of night on using only a bit of tryptophan and her mood is generally excellent. She has osteoporosis and the doctor is not concerned with the florinef impact since she takes 0.1 mg. She jokes that doctors would have to pry Florinef out her cold dead hands before she gave it up.

I do take sea salt. Quite a lot. 1/2 teaspoon per liter, plus I salt my food heavily. I think I'd be dead without the salt, I need it that bad, lol.​

What are your electrolytes like? If you take 1/2 tspn sea salt per liter and assuming 400-500 mg per 1/4 tspn and say 2-3 liters of water a day, that is a LOT of salt. That will certainly amp your CV system and can shift your sleep quality. Your aldosterone could be low since your salt intake is so high. I would be interested in what your recent Comp Metabolic panel results are for Na, K, Cl, etc. That being said if you think the salt is key that is a clear sign of dysautonomia.

I understand your aversion to steroids but Florinef and HC have completely different pharmacological behavior. Florinef is a methylated version of HC that has almost no glucorticoid effects while enhanced mineralcorticoid effects. I don't have time in a post like this to go into all the biology of the different relevant receptors and how they relate to 11 beta HSD1 and the kidney and electrolytes, etc. It can could fill an entire thread practically.

But I will stress that at usual doses of 0.1 mg, florinef has about as much chance of making osteoporosis as taking aspirin (I jest some but only slightly). That is no way to belittle the suffering your mother endured and I am very sorry to hear that. I will also say that if you research dysautonomia (there is a national society for it), florinef is almost always step #1 in treatment followed by the appropriate amount of salt.

In my own case salt saved my life along with Medrol in 2009. My neuroendocrinologist wanted me on Florinef in Spring 2010 and I was reluctant because I did not want another steroid, even though it helped my younger brother greatly. When my Mom needed it in Winter 2012, I caved in an started taking it. I can not describe how much it improved things. It is hard to relate to to others who don't live in my body.

Suddenly I could take sea salt once in the morning only and get by the rest of the day, I went from 2 tspns per day of salt to eventually 1/2 - 3/4 of sea salt after titrating up the Florinef. My potassium suddenly revived (there is a complicated misunderstood relationship there) from near hypokalemic to 4.0+ in the day without altering diet or supplementation and I stopped urinating 12 times or more a day. My BP came down and my heart rate while not awesome came down out of the high 90s and low 100s to say the mid 80s. Also I had MUCH more muscle strength (which gets me into trouble when I think I can do something in say the bedroom (*wink*) or around the house that I should not be attempting these days anyways.

Excess ACh will cause excitotoxicity through NMDA. This is well known. Yes, I do have pain. I get pain from typing, for example. I've had very serious RSI, where my hands turned purple, freezing cold, and I couldn't move my fingers, plus tremendous pain. I'm better now, but yeah I have some pain. I just suck it up, I guess. It's not screaming pain, though.​

Maybe I am being dumb here but I don't know about that connection. I know that NMDA glutamate activity has control actions on ACh release in many parts of the brain but I have never heard of the reverse. Anyway I can't seem to find anything and you seem to have amassed a wonderful treasure trove of articles. Can you link something regarding ACh and NMDA? I am always learning new things

That being said if you are high on ACh, due to lets say reduced ACHe presumably (right?) how much choline and B5 do you take? Those might be double edged swords for you ...

Ok so pain is a clear issue (I have too many bad memories of the screaming variety). So yeah NMDA is certainly a likely culprit especially since a lot of your pain seems nerve related.

How much elemental magnesium do you get a day? That stuff is maybe really key for you since it is your main allosteric switch to down regulate NMDA without using NAC to effectively chelate it. I bet you are ramping GAD activity via your high p5p (I am jealous with my SPS). You might want to check if you are low in lithium, for some that has a huge effect on the glutamate - gaba balance and I think Dr Yasko stated that people with A1298c mutations are at risk for low iodine and lithium. I have not checked my lithium yet but my iodine was dead for until I started Iodoral a year or so ago.

However, a bad vicious norepinephrine / inflammatory cycle can do that too since eventually the muscles' request for laying down new fibers in a catabolic state (been there) is ironically vetoed by a hyper immune system and the signals eventually get translated as pain ... through the NMDA receptors. So see how you can end up at the same place for different reasons. It can be hard to disentangle them.

I only bring this up since I would guess 50% or more of the people on these boards essentially ignore the immune system component when it might be their 800 lb gorilla in the room. And when I mean immune system I mean not simply glutathione, I mean norepinephrine signaling, gut problems, autoimmune, infections, etc. Methylation alone won't make much of dent in the gorilla if those are a problem. It is a pet beef of mine how people ignore the immune system which beyond the workings of the brain is one of the most complicated and vulnerable systems in our body for dysregulation.

The thing is, it's very easy for me to gain weight. Not muscle though, this is hard. But gaining fat is very easy for me.​

If you gain weight then you are not catabolic ... .which is great! The process for gaining fat can be so complicated and multi-factorial I won't touch that conversation with a 10 foot pole. People will foist all sorts of ideas ... I toss my hands up on that one unless someone is say clearly hypothyroid or something.

There are many reasons why someone cannot gain muscle. I am in the midst of that in spades right now and I don't have any answer yet. And my testosterone / DHEA on HRT is better than when I was teenager. My catabolism is probably a combination of gut dysbiosis and my lovely lottery ticket autoimmune disease. Meh. 4000 calories it is!

I will check that out, I just wish I did not only get like 50 mg per pill. Sigh. That means for me it can be at best an adjunct and not a replacement. How much do you take of the Mg-threonate do you take per day?

Thanks for your reply. Take a look at Figure 1 in this article, for the link between ACh and glutamate excitotoxicity. It's true I have amassed a lot of articles, probably 300-400 of them, lol. I'm enrolled in university, so I have access to just about everything. But I'm probably more of a pragmatist than a theorist; I am looking for solutions or treatment options to try. Again, I mostly understand only the principles of what is going on, and not the details. For instance, I don't really know how the methylation cycle works in any detail, I just know it's important, and how to treat it.

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I will agree to having another aldosterone/hormone panel done. But, I am still very scared of steroids, so it will be kind of a last resort for me. I do however agree about the immune system being the big gorilla. In fact, I have argued this in several threads discussing HPAA dysfunction. That is also why it makes more sense to work on the immune system dysfuntion, rather than taking steroids as a crutch. Just my opinion. You really have no other options besides the roids? Rituximab or similar:

I will have more testing done. Not sure which tests, but a hormone panel, and a gut test should be first. It's not easy to get testing here. We have a public health care system, and all test are ordered at the GPs discretion. I haven't been to see a doctor in years, because of their condescending and dismissive reaction to my requests. They probably think I'm a nutcase when I show up with my abstracts and starts discussing biochemistry. Frankly, in my opinion, most doctors haven't got the first clue about how the body works. I am seriously frustrated with doctors. I'd like to just dictate to them what to do, but unfortunately it doesn't seem to work that way, lol. Private labs are also not easy to come by in my area (Scandinavia). I could send blood test by FedEx or similar to the states, at great cost of course, but I still need a doctor to draw the blood. I once convinced a doctor to do a blood sample for a Igenex lyme blot. I had to take my own sample to the hospital lab and convince them to centrifuge it, lol. They lab folks looked at me very strangely. Then Igenex would only give the test result to my doctor, who did not want to accept them. Sigh. I finally convinced him though (it was negative anyway).

Regarding ALCAR, yes I tried other carnitine forms. Only ALCAR works. But it also makes me kind of zombieish and irritable, so I haven't been using it. Maybe we misunderstand each other, but I do not think my AChE is inhibited any longer, I'm sure the pesticides are pretty much out by now. So at this point I believe cholinergics help, probably because they increase signaling at the damaged autonomic ganglia that are not working optimally any more. Again, this is just a guess, I do not know how to test autonomic function. I am sure I have dysautonomia though, I don't need a doctor to tell me that. ALCAR and autonomic neuropathy: http://www.ncbi.nlm.nih.gov/pubmed/11947964

Regarding magnesium threonate, you really can't compare the low dose to other forms, because absorption is much greater. Take a look at these links:

Oh, and regarding the "activity around the house" that have got me into trouble quite a few times also, lol.

I will be trying lithium as you suggest, a mineral test (urine) of mine suggested it is low. I am a little worried about the rat study showing kidney accumulation with lithium orotate, though. But maybe it's safe for humans. Orotic acid has also been linked to cancer in some animal studies.

Yeah the sensitivity and detox card I personally feel gets played way, way too often.

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I've been trying to follow the discussion in this thread though much of it is over my head. Although it's very likely I'm overmethylating, I do believe that I am also experiencing detox symptoms due to mercury toxicity. I am basing my conclusion partially on Rich's posts (although I know even he can be wrong sometimes), but also on accounts other members here with mercury issues who have had similar experiences.

Personally I am finding that 400 mcg 5mthf without vitamin C and still taking 500 mg niacinamide will over-stimulate me and by the third day it builds to insomnia. 200 mcg seems more tenable (though the damn pills are hard to cut). But that is me.

I think mb12 is great, I am not sure I buy into the hydroxy b12, but high mb12 will kill melatonin and induce restlessness. I take a crumb of adb12 per day now. I used to take 1/4 Source naturals every day and at first it made me really sleepy, then amped me like crazy. And that was for several months. That is not a start-up effect. Period.

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I starting taking Niacinamide yesterday in hopes of slowing down my methylation process. I planned on taking 500 mg (divided into 2 doses) plus around 200 mg from my B complex. It looks like I'm going to have to cut back on B12 for awhile. I was taking mostly hydroxocobalamin, but also some adb12 from a Source Naturals sublingual B complex. I didn't think hydroxocobalamin would give me problems, but I think it is a contributing factor and just today I read an account of someone else that had a similar experience with hydroxy b12.

For me it seems that the effects of methylation build over time, but if I stop or cut back for a few days until things settle down a bit and then resume methylation then I do have a reaction. I suppose that's not exactly the same as start up though.

I've been trying to follow the discussion in this thread though much of it is over my head. Although it's very likely I'm overmethylating, I do believe that I am also experiencing detox symptoms due to mercury toxicity. I am basing my conclusion partially on Rich's posts (although I know even he can be wrong sometimes), but also on accounts other members here with mercury issues who have had similar experiences.

I starting taking Niacinamide yesterday in hopes of slowing down my methylation process. I planned on taking 500 mg (divided into 2 doses) plus around 200 mg from my B complex. It looks like I'm going to have to cut back on B12 for awhile. I was taking mostly hydroxocobalamin, but also some adb12 from a Source Naturals sublingual B complex. I didn't think hydroxocobalamin would give me problems, but I think it is a contributing factor and just today I read an account of someone else that had a similar experience with hydroxy b12.

For me it seems that the effects of methylation build over time, but if I stop or cut back for a few days until things settle down a bit and then resume methylation then I do have a reaction. I suppose that's not exactly the same as start up though.

Also, what does Mn stand for?

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I think heavy metal detox certainly can be a valid thing. Not saying otherwise, but ... I also think it is often an over-used crutch. I personally don't trust heavy metal urine tests that are done with a chelating agent. It may be accurate for certain heavy metals but it notoriously wrong for others (WAY too many false positives). I think if a person has validation from 24 hour urine tests, possibly for certain metals also a hair analysis, while others need serum, and have the clinical symptoms then sure there can be an issue.

But just like when bringing a murder case to trial, heavy metals need a motive, i.e. a reason. Like radium in the water. Eating tons of fish in your diet. And so on. There probably is for some a correlation with low glutathione and heavy metals but it is not an absolute correlation. And yes amalgams can be a problem, but I am sorry amalgams are not the root cause of all medical evil as some practitioners tout.

Ergo all I suggest is caution.

I had a doctor for years who was convinced I had mercury poisoning. I never showed abnormal Hg on a single test of ANY type. I never had any 'motive'. Heck I did not even have the symptoms. Did not matter. Finally because I did not know any better at the time and was suffering from my autoimmune disease, I agreed to do a chelation series of treatments. Of course the first chelation wiped me out in my weakened state. They are hard on the body for anyone. As a physicist I asked the doctor to examine the chelated liquid and even though he had drilled me with a really high amount of several chelating agents, my Hg was well in normal. Needless to say I did not do any more chelation.

The other place where Herxheimer makes sense is with infections and gut dysbiosis. But that doesn't mean you can apply that logic to every other biological pathway.

Sometimes people here try so hard to use a protocol best suited for someone who has a very different biological / genetic profile and they end up getting devastated and all they receive back is opinions that with time it will get better and these are all start-up or detox effects.

As both a physicist and now 20 years in the bioinformatics and genomics, sorry but I call BS.

Again all I suggest is people step out of the box (hate that phrase but oh well) and look at things from a different perspective. There is not doubt that the folate - methylation - trans-sulfuration cycles are hugely important. Heck unless you study biology, I doubt most people on these forums really know how unbelievably powerful methylation is. You are altering expression patterns, silencing some pathways, altering others. This is fundamental biochemistry. Essentially you are tinkering with the epigenetics which is one step removed from your genome. Is that something we should fiddle with, I think for most of us on here we have no choice and have to do something. But .. the question is how and how much. Again caution.

Every human being will react to methylation changes. They just will react differently. Some people have more defects either functional or genetic. Some pathways have been altered or shunted for years for the person to survive. For me it takes 3-5 days to unravel an over-methylation or to instead feel under-methylated (those terms of course subjective to each individual).

On the way up, I might feel good the first day, but I convince myself it will be different this time, and by the 2nd and certainly the 3rd day I am full force. Note like Adreno, I spent a LONG time overmethylated without realizing what I was doing. So get me wrong it is hard to calibrate things. Again caution.

I myself don't have a clear cut answer for myself on mb12 and hb12. They are just different in some ways and not others. Maybe that is since I don't have the C667 mutation for MTHFR. Dunno. I have to still wait for my 23andMe results before I dig further.

At least I am getting a handle on what affects my urine sulfate values. That has turned out to be a bigger piece of the puzzle than I ever dreamed.

Sigh always learning.

P.S. Mn = manganese. Be careful with that one if you decide to try it. I would advise a test either serum / plasma, urine or hair or two or three of those before you go full out. You can also estimate your diet intake. I forget what the absorption multiplier is. Maybe 30-50%? I will see if I can find something reliable on that.

That is way too much calcium vs way too little magnesium for the types of issues you are describing. Check your diet intake first. Also you are male so Ca requirements are different. Your ratio is way off imho. Not sure how you want to address it.

You might need more vit D in the winter depending on where you live and what your active 1,25 active blood values are, NOT only your inactive 25, values that everyone focuses on (don't get me started on that medical idiocy).

That is a really low amount of DHEA. I am suggesting you take more since HRT I think needs medical supervision. But 10 mg is really insignificant for a man. You are a taking a woman's dose.

That is a lot of monolaurin. Fine. But if you need that then something is really going on in your gut.

Not familiar with zinc carnosine but that is a hefty amount of zinc if you take 60, especially with the 500 mcg Mo.

If 100 mg of GABA affects you then you have leaky BBB.

That is a lot of NAC. I know if helps you. Need to better understand why it is so crucial to you.

That amount of fish oil is excellent. Nordic Naturals is a good brand imo.

That is a really low dose of CoQ10. If you like it take that amount 2-3x a day.

How do you like the benfotiamine for m of B1?

That is a decent dose of TMG but it probably is needed with your CBS and BHMT SNPs. The BHMT pathway is infamous for imbalancing the norepinephrine and dopamine balance in favor of norepinephrine.

To answer your other question, ignoring cost, I would not touch the rituximab with a 10 foot pole. There are to my understanding some nasty different side effects. For now at least I will take my chances with the glucocorticoids. That may change in the future.

Curious which brand of R-ALA did you use? How big of difference did you see for yourself for R-ALA for racemic mixture for roughly equivalent doses (theory aside). 300 mg of R-ALA is fairly potent is it not?